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IntroductionDespite unprecedented pressures on urgent and emergency care services, there is no clear consensus on how to provide acute medical care delivery in the UK. These pressures can lead to significant delays in care for patients presenting with emergencies when admitted via traditional routes through the emergency department. Historically, a separate pathway has existed where patients are directly admitted to acute medicine services without attending the emergency department. It is suspected that there is a significant variation in how these patients are selected, triaged and managed in the UK. This systematic review will assess the methods and evidence base used for direct patient admissions to acute medicine services compared with traditional admission pathways through the emergency department.Methods and analysisA systematic review of the literature will be conducted and a total of six databases will be searched: MEDLINE (Ovid), The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE in process, Web of Science, CINAHL and Embase. This will include studies from the period 01 January 1975 to 24 January 2024. Covidence software will be the platform for the extraction of data and paper screening with the selection process reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram. Both title and abstract screening and full-text screening will be done by two reviewers independently. The risk of bias of included studies will be assessed using the methods introduced in the Cochrane Handbook for Systematic Reviews of Interventions and the tool used will be dependent on the type of study. Where possible, outcomes will be dealt with as continuous variables. Change percentage will be assessed between any pathway characteristic or outcome. The χ² test and I² test will be used to evaluate the heterogeneity of included studies. Where appropriate, relevant meta-analysis techniques will be used to compare studies and forest plot produced.Ethics and disseminationThis systematic review does not require ethical approval. Findings will be disseminated widely in peer-reviewed publication and media, including conferences.PROSPERO registration numberCRD42023495786.

For nearly 400 million years, insects and plants have been embattled in an evolutionary arms race. Insects have developed diverse feeding strategies and behaviors in an effort to circumvent and overcome an extensive collection of plant defense tactics. Sap-sucking insects often inject saliva into hosts plants, which contains a suite of effector proteins and even microbial communities that can alter the plant's defenses. Lacking salivary glands, leaf-feeding beetles represent an interesting group of phytophagous insects. Feeding beetles regurgitate onto leaf surfaces and it is thought that these oral secretions influence insect-plant interactions and even play a role in virus-vector specificity. Since the molecular and biological makeup of the regurgitant is virtually unknown, we carried out RNA sequencing and 16S rDNA analysis on a major soybean pest, Epilachna varivestis, to generate the first ever beetle \"regurgitome\" and characterize its microbiome. Interestingly, the regurgitant is comprised of a rich molecular assortment of genes encoding putative extracellular proteins involved in digestion, molting, immune defense, and detoxification. By carrying out plant inoculation assays, we reinforced the fundamental role of the regurgitant in beetle-borne virus specificity. Ultimately, these studies begin to characterize the importance of regurgitant in virus transmission and beetle-plant interactions.

Background Improved understanding of psychosocial factors associated with alcohol use in lower socioeconomic position (SEP) populations could inform theory and practice in the development of interventions aimed at reducing alcohol-related harm in this population. This review aimed to review and synthesise the literature on these associations for lower SEP populations. Methods We conducted a scoping review of studies examining associations between psychosocial factors and alcohol use in lower SEP populations. Web of Science (Core Collection), Scopus, Embase (Embase and Medline), PubMed, and APAPsycNet (PsycInfo) were searched. Out of 6597 identified articles, 26 articles were included from the databases. Hand searching of references of these studies identified four additional eligible studies. Narrative synthesis was used to synthesise identified factors. Results 30 studies in total (21 quantitative, nine qualitative) were included. Identified psychosocial factors related to mental health, stress, drinking motives, alcohol availability, adolescence, cognitive factors, and other psychosocial factors. Conclusions The array of identified psychosocial factors can inform future directions for tailored alcohol interventions for lower SEP populations. The evidence base is predominantly comprised of quantitative studies investigating factors such as mental health and stress. Future research in the area would benefit from greater use of qualitative studies to complement these insights and generate improved understanding of experiences of alcohol use among lower SEP populations. Individual-level drinking motivations (e.g., coping with stress and mental health) may be amplified by the environmental context of disadvantaged neighbourhoods, which may play a role in disposition to drinking as a coping mechanism. Yet, these communities may have reduced access to alternative coping resources. Policymakers implementing population-level interventions to reduce alcohol availability may also need to consider what and how alternative coping resources and strategies for stress and mental health can be implemented in underserved communities. Targeting specific drinking reasons may increase intervention acceptability among lower SEP populations.

The maritime expansion of Scandinavian populations during the Viking Age (about ad  750–1050) was a far-flung transformation in world history 1 , 2 . Here we sequenced the genomes of 442 humans from archaeological sites across Europe and Greenland (to a median depth of about 1×) to understand the global influence of this expansion. We find the Viking period involved gene flow into Scandinavia from the south and east. We observe genetic structure within Scandinavia, with diversity hotspots in the south and restricted gene flow within Scandinavia. We find evidence for a major influx of Danish ancestry into England; a Swedish influx into the Baltic; and Norwegian influx into Ireland, Iceland and Greenland. Additionally, we see substantial ancestry from elsewhere in Europe entering Scandinavia during the Viking Age. Our ancient DNA analysis also revealed that a Viking expedition included close family members. By comparing with modern populations, we find that pigmentation-associated loci have undergone strong population differentiation during the past millennium, and trace positively selected loci—including the lactase-persistence allele of LCT and alleles of ANKA that are associated with the immune response—in detail. We conclude that the Viking diaspora was characterized by substantial transregional engagement: distinct populations influenced the genomic makeup of different regions of Europe, and Scandinavia experienced increased contact with the rest of the continent. Ancient DNA analyses reveal that Viking Age migrations from Scandinavia resulted in differential influxes of ancestry to different parts of Europe, and the increased presence of non-local ancestry within Scandinavia.

Background Despite progress, stillbirth rates in many high- and upper-middle income countries remain high, and the majority of these deaths are preventable. We introduce the Ending Preventable Stillbirths (EPS) Scorecard for High- and Upper Middle-Income Countries, a tool to track progress against the Lancet’s 2016 EPS Series Call to Action, fostering transparency, consistency and accountability. Methods The Scorecard for EPS in High- and Upper-Middle Income Countries was adapted from the Scorecard for EPS in Low-Income Countries, which includes 20 indicators to track progress against the eight Call to Action targets. The Scorecard for High- and Upper-Middle Income Countries includes 23 indicators tracking progress against these same Call to Action targets. For this inaugural version of the Scorecard, 13 high- and upper-middle income countries supplied data. Data were collated and compared between and within countries. Results Data were complete for 15 of 23 indicators (65%). Five key issues were identified: (1) there is wide variation in stillbirth rates and related perinatal outcomes, (2) definitions of stillbirth and related perinatal outcomes vary widely across countries, (3) data on key risk factors for stillbirth are often missing and equity is not consistently tracked, (4) most countries lack guidelines and targets for critical areas for stillbirth prevention and care after stillbirth and have not set a national stillbirth rate target, and (5) most countries do not have mechanisms in place for reduction of stigma or guidelines around bereavement care. Conclusions This inaugural version of the Scorecard for High- and Upper-Middle Income Countries highlights important gaps in performance indicators for stillbirth both between and within countries. The Scorecard provides a basis for future assessment of progress and can be used to help hold individual countries accountable, especially for reducing stillbirth inequities in disadvantaged groups. Key messages 1. Wide disparities in stillbirth rates exist between and within high- and upper-middle income countries, indicating that further reduction in stillbirth rates is possible. The existence of disparities in stillbirth rates across high- and upper-middle income countries shows that further improvements in stillbirth prevention are possible and makes the continued reduction of stillbirth rates a public health imperative. This includes balanced measures to ensure that stillbirth prevention strategies do not result in an increase in related perinatal outcomes, such as preterm birth and neonatal death. 2. Numerous disparate national stillbirth definitions are used in high- and upper-middle income countries, limiting comparisons necessary to drive change. The use of multiple definitions for stillbirth and related perinatal outcomes makes it difficult to assess and compare individual countries’ performance, and to use data for advocacy and accountability for stillbirth prevention and support. Universal definitions specific to high- and upper-middle income countries should be developed and used. 3. Data on key risk factors and equity in stillbirth rates are limited, however, underline the need for increased focus on the most affected communities. Tracking stillbirth rates associated with risk factors such as socio-economic deprivation and adolescent, or unplanned pregnancies can help in the development, adaptation and implementation of stillbirth prevention strategies. Yet these data are often lacking. Similarly, data on equity in stillbirth and related birth outcomes can help to inform stillbirth prevention strategies; however, such data are frequently unavailable, contributing to insufficient targeting of at-risk populations. National equity targets for birth outcome are required. 4. Most high- and upper-middle income countries lack guidelines and targets on key areas critical for stillbirth prevention and care after stillbirth, including national stillbirth rate targets. The absence of guidelines and targets on key areas critical for stillbirth prevention and care after stillbirth means healthcare providers, civil society and other stakeholders have no benchmarks or criteria to hold the healthcare system accountable or to measure quality of care. We identified several targets that could be incorporated into guidance for improved quality of care, including setting of national stillbirth rate targets. 5. Most high- and upper-middle income countries do not have guidelines around bereavement care, or mechanisms in place for reduction of stigma. Stigma enables the perpetuation of common myths around stillbirth, such as the belief that stillbirth is inevitable. Putting mechanisms in place to reduce stigma and developing guidelines for appropriate bereavement care should be a priority.

Human immunodeficiency virus (HIV)-1-specific broadly neutralizing monoclonal antibodies are currently under development to treat and prevent HIV-1 infection. We performed a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial of a single administration of the HIV-1 V3-glycan-specific antibody PGT121 at 3, 10 and 30 mg kg –1 in HIV-uninfected adults and HIV-infected adults on antiretroviral therapy (ART), as well as a multicenter, open-label trial of one infusion of PGT121 at 30 mg kg –1 in viremic HIV-infected adults not on ART (no. NCT02960581). The primary endpoints were safety and tolerability, pharmacokinetics (PK) and antiviral activity in viremic HIV-infected adults not on ART. The secondary endpoints were changes in anti-PGT121 antibody titers and CD4 +  T-cell count, and development of HIV-1 sequence variations associated with PGT121 resistance. Among 48 participants enrolled, no treatment-related serious adverse events, potential immune-mediated diseases or Grade 3 or higher adverse events were reported. The most common reactions among PGT121 recipients were intravenous/injection site tenderness, pain and headache. Absolute and relative CD4 +  T-cell counts did not change following PGT121 infusion in HIV-infected participants. Neutralizing anti-drug antibodies were not elicited. PGT121 reduced plasma HIV RNA levels by a median of 1.77 log in viremic participants, with a viral load nadir at a median of 8.5 days. Two individuals with low baseline viral loads experienced ART-free viral suppression for ≥168 days following antibody infusion, and rebound viruses in these individuals demonstrated full or partial PGT121 sensitivity. The trial met the prespecified endpoints. These data suggest that further investigation of the potential of antibody-based therapeutic strategies for long-term suppression of HIV is warranted, including in individuals off ART and with low viral load. A single dose of a broadly neutralizing, HIV-specific antibody transiently reduces viral load in plasma, and in some individuals is associated with durable virus suppression in the absence of antiretroviral therapy.

The adoption of whole genome sequencing (WGS) in clinical oncology is challenged by low data quality and increased artifacts in standard-of-care formalin-fixed paraffin-embedded (FFPE) samples. Analysis of 56 fresh frozen (FF) and FFPE matched pairs demonstrates that FFPE processing results in a median 20-fold enrichment in artifactual calls across mutation classes and impairs detection of clinically relevant biomarkers such as homologous recombination deficiency (HRD). We demonstrate that implementation of consensus calling reduces artifactual structural variant (SV) calls by 98% but is not sufficient in mitigating artifactual calls for single nucleotide variants (SNVs) and indels as compared to FF data. We develop FFPErase, a machine learning framework that filters SNV/indel artifacts and delivers clinical grade variant reporting allowing accurate quantification of clinically relevant biomarkers. Comparison of FFPErase WGS calls to clinical reporting by FDA-approved panel tests demonstrates 99% sensitivity and enables reporting of 24% more clinically relevant findings.

Background/Objectives:Growing evidence suggests that antibiotic use is associated with childhood body mass index (BMI), potentially via mechanisms mediated by gut microbiome alterations. Less is known on the potential role of prenatal antimicrobial use in offspring obesity risk. We examined whether prenatal antibiotic or antifungal use was associated with BMI at the age of 2 years in 527 birth cohort participants.Methods/Subjects:Antimicrobial use was obtained from the prenatal medical record. Height and weight were measured at the age of 2 years. Overweight/obesity was defined as a BMI [egs]85th percentile.Results:A total of 303 (57.5%) women used antibiotics and 101 (19.2%) used antifungals during pregnancy. Prenatal antifungal use was not associated with child BMI at the age of 2 years. In the fully adjusted model, prenatal antibiotic use was associated with a 0.20±0.10 (P=0.046) higher mean BMI Z-score at the age of 2 years. Associations between prenatal antibiotic use and childhood BMI varied by trimester of exposure, with first or second-trimester exposure more strongly associated with larger BMI at the age of 2 years for both BMI Z-score (interaction P=0.032) and overweight/obesity (interaction P=0.098) after covariate adjustment.Conclusions:Prenatal antibiotic, but not antifungal, use is associated with larger BMI at the age of 2 years; associations were stronger for antibiotic exposures in earlier trimesters. Future studies examining whether these associations are due to alterations in the maternal and/or infant microbiome are necessary. Children who are overweight at the age of 2 years are at higher risk for being overweight as they age; prenatal antibiotic use is a potentially modifiable exposure that could reduce childhood obesity.

Purpose INHALE investigated the impact of seeking pathogens by PCR on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia (HAP and VAP). Methods This pragmatic multicentre, open-label RCT enrolled adults and children with suspected HAP and VAP at 14 ICUs. Patients were randomly allocated to standard of care, or rapid in-ICU syndromic PCR coupled with optional prescribing guidance. Co-primary outcomes were superiority in antibiotic stewardship at 24 h and non-inferiority in clinical cure of pneumonia 14 days post-randomisation. Secondary outcomes included mortality, ICU length of stay and evolution of clinical scores. Results 554 eligible patients were recruited from 5th July 2019 to 18th August 2021, with a COVID-enforced pause from 16th March 2020 and 9th July 2020. Data were analysed for 453 adults and 92 children (68.4% male; 31.6% female). ITT analysis showed 205/268 (76.5%) reviewable intervention patients receiving antibacterially appropriate and proportionate antibiotics at 24 h, versus 147/263 (55.9%) standard-of-care patients (estimated difference 21%; 95% CI 13–28%). However, only 152/268 (56.7%) intervention patients were deemed cured of pneumonia at 14 days, versus 171/265 (64.5%) standard-of-care patients (estimated difference − 6%, 95% CI − 15 to 2%; predefined non-inferiority margin -13%). Secondary mortality and ΔSOFA outcomes narrowly favoured the control arm, without clear statistical significance. Conclusions In-ICU PCR for pathogens resulted in improved antibiotic stewardship. However, non-inferiority was not demonstrated for cure of pneumonia at 14 days. Further research should focus on clinical effectiveness studies to elucidate whether antibiotic stewardship gains achieved by rapid PCR can be safely and advantageously implemented.